Autophagy Selectively Degrades Asymmetrically Dimethylarginated Proteins Induced By Cytokines In Tumor Cells

Protein arginine methylation is a common posttranslational modification resulting in the generation of asymmetric dimethylarginine(aDMA)and symmetric dimethylarginine(sDMA).However,the regulation of these two types of modified proteins has not been investigated well in cancer cell.Here,we report that the proteins modified by aDMA or sDMA are mainly detected in cancer cells with molecular mass of 90,70,55 or 34 kDa.Among them,p90 aDMA is specially up-regulated by IL-2,IL-4 and IL-6,but not by IL-8,all of which may be enriched in tumor microenvironments.The up-regulation is blocked by adenosine-2?,3?-dialdehyde(AdOx),a global methyltrasferase inhibitor.Both p90 aDMA and p70 aDMA are exclusively accumulated in the nucleus of cancer cells and degraded by hypoxia,nutrients starvation or rapamycin.The degradation is mediated by autophagy selectively sensing aDMA,because it can be reversed by 3-Methyladenine(3MA)and siRNA specific for autophagy-related gene 5(ATG5).Taken together,our results add a new dimension to the complexity of dimethylated arginine-mediated regulation in response to various stimuli and provide the first evidence that aDMA serves as a specific degradation signal of selective autophagy.